We propose to integrate molecular biology, morphometry, and clinical studies to identify mechanisms leading to abnormal brain development, accelerated aging, and early onset of Alzheimer disease in people with Down syndrome (DS). We plan to conduct biochemical and morphometric studies of the memory system (hippocampus, amygdala, and entorhinal cortex) and sensory-motor system ( substantia nigra, pedunculopontine tegmental nucleus, caudal intralaminar thalamus, caudate nucleus, putamen, globus pallidus, nucleus accumbens, motor cortex, and cerebellum) in 44 people with DS. Because all people with DS develop early onset AD and some develop parkinsonian-type neurodegeneration, the mechanisms of neuronal loss in DS will be compared with temporal and topographic patterns of neuronal degeneration and loss in sporadic AD (30 cases), idiopathic PD (30 cases), and normal aging (44 cases). Our goal will be to determine: (1) the role of abnormal expression of Mnbk/DyrklA in developmental neuronal deficits in the memory and motor system of people with DS; (2) the mechanisms of synaptic abnormalities caused by excess of Mnbk/Dyrk1A protein in people with DS; (3) the role of Mnbk/Dyrk1A protein in brain accelerated aging during the fourth decade of life in people with DS; (4) the contribution of different mechanisms of neurodegeneration to dementia and motor deterioration in people with DS over 40 years of age; (5) modifications in the contribution of neurodegenerative changes to neuronal and functional loss in people with DS in comparison to normal aging, sporadic AD, and idiopathic PD. We hypothesize that in DS the extra copy of the Mnbk/Dyrk1A gene is not only a key factor in shaping structural and functional developmental abnormalities, but also affects the function of synapses in adulthood, contributes to accelerating aging of the brain, and changes the structural and functional background for development of AD and PD pathology. We hypothesize that we will be able to identify DS-specific modifications of the course of AD and PD pathology. This study will provide a foundation for identifying the mechanisms and morphological substrate of specific functional deficits, and should contribute to the improvement of diagnosis and treatment.